Lee Kyung, He John Cijiang
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Renal Section, James J. Peters Veterans Affair Medical Center, 130 W. Kingsbridge Road, Bronx, NY, 10468, USA.
Fac Rev. 2022 Jul 28;11:21. doi: 10.12703/r/11-21. eCollection 2022.
Although albuminuria development is considered the natural course of diabetic kidney disease (DKD), increasing evidence indicate that the disease can present as non-albuminuric DKD (NA-DKD), characterized by prominent tubulointerstitial injury and fibrosis without obvious glomerulopathy. However, the pathogenic mechanisms underlying NA-DKD remain unclear. As diabetic patients are more susceptible to acute kidney injury (AKI), and the maladaptive repair of kidney tubules following AKI occurs more frequently in diabetic than non-diabetic patients, the enhanced AKI-to-CKD transition may be a significant contributor of NA-DKD. Recent studies indicate that endoplasmic reticulum (ER) stress is a key pathogenic driver of AKI-to-CKD transition, and that the tubular expression of ER-resident protein reticulon 1A (RTN1A) correlates with human DKD progression and AKI-to-CKD transition. Experimental studies showed that RTN1A indeed mediates tubular cell injury and AKI-to-CKD transition in diabetic mice via concomitant activation of ER stress and mitochondrial dysfunction as a mediator of ER-mitochondrial crosstalk. Further understanding of the pathogenesis of tubular injury in DKD will help us to develop sensitive and specific biomarkers or diagnostic tools to distinguish between injury-related AKI, pre-renal AKI from hemodynamic changes, and the progression of DKD in order to better manage patients with DKD.
尽管蛋白尿的出现被认为是糖尿病肾病（DKD）的自然病程，但越来越多的证据表明，该疾病可以表现为非蛋白尿性DKD（NA-DKD），其特征是肾小管间质损伤和纤维化明显，而无明显的肾小球病变。然而，NA-DKD的致病机制仍不清楚。由于糖尿病患者更容易发生急性肾损伤（AKI），并且与非糖尿病患者相比，糖尿病患者AKI后肾小管的适应性修复更频繁地发生不良，因此AKI向慢性肾脏病（CKD）的转化增强可能是NA-DKD的一个重要促成因素。最近的研究表明，内质网（ER）应激是AKI向CKD转化的关键致病驱动因素，并且ER驻留蛋白网织蛋白1A（RTN1A）的肾小管表达与人类DKD进展和AKI向CKD的转化相关。实验研究表明，RTN1A确实通过伴随激活ER应激和线粒体功能障碍作为ER-线粒体串扰的介质，介导糖尿病小鼠的肾小管细胞损伤和AKI向CKD的转化。进一步了解DKD中肾小管损伤的发病机制将有助于我们开发敏感和特异的生物标志物或诊断工具，以区分损伤相关的AKI、血流动力学变化引起的肾前性AKI以及DKD的进展，从而更好地管理DKD患者。
